ACS Medicinal Chemistry Letters最新文献_第6页

Novel Azepinoindoles as 5-HT2C Agonists for Treating Depression, Drug Addiction, Alcoholism, PTSD, and Neuropathic Pain 新型氮平吲哚作为5-HT2C激动剂治疗抑郁症、药物成瘾、酒精中毒、创伤后应激障碍和神经性疼痛

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-28 DOI: 10.1021/acsmedchemlett.5c00426

Ram W. Sabnis*,

引用次数: 0

Carbamates with ortho-Substituted O-Phenyl Groups as Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: Inhibitory Potency, Hydrolytic Stability, and QSAR Studies 邻位取代邻苯基氨基甲酸酯作为脂肪酸酰胺水解酶和单酰基甘油脂肪酶的双重抑制剂：抑制效力、水解稳定性和QSAR研究

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-24 DOI: 10.1021/acsmedchemlett.5c00233

Tim Depmeier, Walburga Hanekamp and Matthias Lehr*,

{"title":"Carbamates with ortho-Substituted O-Phenyl Groups as Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: Inhibitory Potency, Hydrolytic Stability, and QSAR Studies","authors":"Tim Depmeier, Walburga Hanekamp and Matthias Lehr*, ","doi":"10.1021/acsmedchemlett.5c00233","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00233","url":null,"abstract":"The serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are key enzymes in the degradation of endocannabinoids, which regulate numerous physiological processes. Their role in maintaining endocannabinoid balance makes them promising targets for treating neurological disorders. We synthesized a series of 6-(5-phenyltetrazolylhexyl)carbamates bearing O-phenyl residues with various ortho-substituents. Inhibition of FAAH and MAGL was found to depend on the inductive and electronic properties of these substituents. Electron-withdrawing groups increase carbamate reactivity, promoting faster covalent bonding with the catalytic serine in the enzymes’ active sites. However, this also raises the compounds’ susceptibility to hydrolysis. Quantitative structure–activity relationship (QSAR) analysis revealed a strong logarithmic correlation between FAAH inhibition of compounds with uncharged ortho-substituents, expressed as logIC50, and the electron-withdrawing effect of theses residues, measured by the Hammett sigma (σ) constant. Conversely, this correlation allows estimation of unknown Hammett constants from the FAAH inhibition data of suitably substituted carbamates.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1601–1609"},"PeriodicalIF":4.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel Isoindolinone-Containing PARP Inhibitors: Synthesis and Therapeutic Applications in CNS Cancer Treatment 新型异吲哚酮类PARP抑制剂的合成及其在中枢神经系统肿瘤治疗中的应用

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-24 DOI: 10.1021/acsmedchemlett.5c00410

Xin Zhou, and , Steven H. Liang*,

引用次数: 0

Proline Homologation in Melanostatin Neuropeptide: Discovery of Potent Modulators of the Dopamine D2 Receptors 黑素抑素神经肽中的脯氨酸同源性：多巴胺D2受体的有效调节剂的发现

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-24 DOI: 10.1021/acsmedchemlett.5c00287

Ivo E. Sampaio-Dias*, Hugo F. Costa-Almeida, Xavier C. Correia, Sara C. Silva-Reis, Vera M. Costa, José Brea, María I. Loza, José E. Rodríguez-Borges and Xerardo García-Mera,

{"title":"Proline Homologation in Melanostatin Neuropeptide: Discovery of Potent Modulators of the Dopamine D2 Receptors","authors":"Ivo E. Sampaio-Dias*, Hugo F. Costa-Almeida, Xavier C. Correia, Sara C. Silva-Reis, Vera M. Costa, José Brea, María I. Loza, José E. Rodríguez-Borges and Xerardo García-Mera, ","doi":"10.1021/acsmedchemlett.5c00287","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00287","url":null,"abstract":"Melanostatin (MIF-1) is a naturally occurring neuropeptide acting as a positive allosteric modulator (PAM) of dopamine D2 receptors (D2R), underscoring its potential for therapeutic use in central nervous system disorders associated with dopaminergic dysregulation, including depression, drug addiction, restless legs syndrome, tardive dyskinesia, and Parkinson’s disease. In this work, a new series of MIF-1 analogs using l-pipecolic acid as an l-proline surrogate was synthesized and pharmacologically evaluated by functional assays at the D2R. In this series, methyl l-pipecolyl-l-leucylglycinate (9) was found to exhibit superior performance compared to MIF-1 by promoting a 4.1- and 4.2-fold increase of dopamine potency at 0.01 and 1 nM, respectively. In silico conformational studies demonstrate that 9 preferentially adopts a γ-turn, corroborating that neither the C-terminal carboxamide nor the postulated type II β-turn conformation is required for PAM activity. Toxicological assays in human dopaminergic SH-SY5Y neuronal cells show that this compound exhibits no significant toxicity up to 100 μM in the MTT reduction and neutral red uptake assays.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1437–1444"},"PeriodicalIF":4.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preparation of Novel PARP1 Inhibitors and Their Use in Cancer Treatment 新型PARP1抑制剂的制备及其在癌症治疗中的应用

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-23 DOI: 10.1021/acsmedchemlett.5c00411

Xin Zhou, and , Steven H. Liang*,

引用次数: 0

Desulfinative Cross-Coupling as a Method to Overcome Problematic Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heteroaromatic Boronates 以脱硫交叉偶联法解决药物相关杂芳硼酸盐的Suzuki-Miyaura反应问题

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-23 DOI: 10.1021/acsmedchemlett.5c00327

David C. Blakemore, Andre Shavnya* and Michael C. Willis*,

{"title":"Desulfinative Cross-Coupling as a Method to Overcome Problematic Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heteroaromatic Boronates","authors":"David C. Blakemore, Andre Shavnya* and Michael C. Willis*, ","doi":"10.1021/acsmedchemlett.5c00327","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00327","url":null,"abstract":"The well documented difficulties associated with direct (hetero)arylation of aza-aromatics (e.g., azines) at the α-position to nitrogen led to a collaborative project between the Willis group at Oxford and the Medicine Design department at Pfizer with the aim of addressing this challenge. The result of this collaboration has been a series of reports detailing the development of 2-aza-aryl sulfinates, as well as related 2-aza-aryl sulfone derivatives, as efficient nucleophilic reagents in palladium-catalyzed coupling reactions with (hetero)aryl halides. The developed chemistry is routinely used in the medicinal chemistry laboratories at Pfizer, and the patent literature now contains many examples of these methods being embraced across the pharmaceutical industry. Hundreds of pyridyl (and related heterocyclic) sulfinates are now commercially available from multiple vendors. In this microperspective we discuss the development and evolution of these methods and highlight subsequent applications.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1463–1472"},"PeriodicalIF":4.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00327","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GPepT: A Foundation Language Model for Peptidomimetics Incorporating Noncanonical Amino Acids GPepT：包含非规范氨基酸的拟肽学的基础语言模型

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-22 DOI: 10.1021/acsmedchemlett.5c00375

Yuna Oikawa, Takanori Uzawa, Francois Berenger, Noriko Minagawa, Akiko Yumoto, Hideaki Takaku, Ryo Tamura, Yoshihiro Ito and Koji Tsuda*,

{"title":"GPepT: A Foundation Language Model for Peptidomimetics Incorporating Noncanonical Amino Acids","authors":"Yuna Oikawa, Takanori Uzawa, Francois Berenger, Noriko Minagawa, Akiko Yumoto, Hideaki Takaku, Ryo Tamura, Yoshihiro Ito and Koji Tsuda*, ","doi":"10.1021/acsmedchemlett.5c00375","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00375","url":null,"abstract":"Language models have been increasingly popular in therapeutic peptide generation, but molecular diversity remains limited due to reliance on the 20 canonical amino acids. We propose a language model that generates peptidomimetics incorporating noncanonical elements like noncanonical amino acids and terminal modifications. To accomplish this, we created a vocabulary of over 17,000 noncanonical elements by extracting them from chemical formulas stored in the ChEMBL database. Our pretrained language model, GPepT, showed improved diversity in molecular structures and chemical properties. To demonstrate its real-world application, we fine-tuned the model for antimicrobial peptides. Experimental validation revealed that one of the generated peptidomimetics exhibited effective antimicrobial activity, marking a successful case of AI-driven peptide development. GPepT is fully accessible on HuggingFace: https://huggingface.co/Playingyoyo/GPepT.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1670–1675"},"PeriodicalIF":4.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00375","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

64Cu-Labeled Boronic-Acid-Conjugated Porphyrin: A Novel Agent for PET Imaging and Boron Neutron Capture Therapy 64cu标记的硼酸共轭卟啉：一种用于PET成像和硼中子俘获治疗的新型药物

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI: 10.1021/acsmedchemlett.5c00146

Jae Hun Ahn, Changkeun Im, Soyeon Kim, Iqra Bibi, In Ok Ko, Yong Jin Lee, Ji-Ae Park* and Choong Mo Kang*,

{"title":"64Cu-Labeled Boronic-Acid-Conjugated Porphyrin: A Novel Agent for PET Imaging and Boron Neutron Capture Therapy","authors":"Jae Hun Ahn, Changkeun Im, Soyeon Kim, Iqra Bibi, In Ok Ko, Yong Jin Lee, Ji-Ae Park* and Choong Mo Kang*, ","doi":"10.1021/acsmedchemlett.5c00146","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00146","url":null,"abstract":"Radiometal-labeled porphyrin derivatives have emerged candidates for targeted brain tumor imaging and therapy. In this study, we synthesized a boronic-acid-conjugated porphyrin and radiolabeled it with 64Cu to evaluate its dual-function potential for PET imaging and boron neutron capture therapy (BNCT). The 64Cu-labeled 5,10,15,20-(tetra-4-dihydroxyborylphenyl)porphyrin ([64Cu]Cu-TDBP) exhibited excellent serum stability and significant uptake in U87MG cells. PET imaging in both xenograft and orthotopic models demonstrated time-dependent tumor accumulation, with selective localization in the brain tumor at 18 h post-injection (p.i.). The tumor-to-brain ratio increased from 7.2 at 4 h p.i. to 26.3 at 18 h p.i., alongside a rise in tumor boron concentration from 0.79 to 1.83 ppm over the same period. These results highlight the potential of [64Cu]Cu-TDBP as a promising theranostic agent for precise brain tumor imaging and effective BNCT.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1533–1537"},"PeriodicalIF":4.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and Development of Potent SOS1 Inhibitors with Effective Antitumor Activities In Vitro/In Vivo 体外/体内具有有效抗肿瘤活性的强效SOS1抑制剂的设计和开发

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI: 10.1021/acsmedchemlett.5c00152

Xudong Pang, Dawei Cui, Qing Zhang, Hui Liang, Ruifeng Liu, Binhua Lv* and Cheng-Yun Wang*,

引用次数: 0

Novel Compounds as SMARCA2 Inhibitors for Treating Non-small Cell Lung Cancer 新化合物作为SMARCA2抑制剂治疗非小细胞肺癌

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-18 DOI: 10.1021/acsmedchemlett.5c00419

Ram W. Sabnis*,

引用次数: 0